The overall objective of Dr. Mingye Feng?s research proposal is to understand the underlying mechanism of macrophage-mediated immunosurveillance in cancer development and metastasis. The understanding of the mechanisms by which T, B and NK cells detect and attack tumor cells has enabled the development of immunotherapies as promising therapeutics for cancer. Recently, the important roles of macrophages in the surveillance and elimination of tumor cells, which was termed ?programmed cell removal? (PrCR), have begun to be revealed. The upregulation of anti-phagocytic ?don?t eat me? signals on cancer cells protects them from PrCR, while blockade of such pathways enables PrCR and leads to the elimination of cancer cells by macrophages. Inducing macrophage-mediated immunosurveillance holds considerable promise for the treatment of various cancers. The proposed research will focus on understanding the underlying mechanism of PrCR and developing strategies to promote PrCR of metastatic cancer cells. Specific aim1 is to determine the molecular machinery of macrophage-cancer cell interaction, by dissecting the molecular mechanisms of cancer cell recognition during the initiation of PrCR and determining the function and regulation of subpopulations of tumor-associated macrophages involved in pro-and anti-tumorigenic functions. Specific aim2 is focused on understanding the anti-PrCR self-protective mechanisms of metastatic cancer cells and developing strategies to induce their elimination by exploiting the tumoricidal role of PrCR. Dr. Feng has generated publishable results and developed the in vitro and in vivo selection models during the K99 phase and is preparing manuscripts. He will conduct research in the R00 phase as an independent principle investigator at the Beckman Research Institute of City of Hope National Medical Center. During the R00 phase, he will collect publishable data on the proposed research and start applying for R01 grant at the end of the first year. His research during the R00 phase will receive full support from City of Hope which will provide an outstanding environment to foster his career development and application of independent research grants.